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Published on: February 16, 2015
An engineering strategy to target activated EGFR with CAR T cells
Markus Dobersberger1, Delia Sumesgutner2, Charlotte U Zajc2
1Department of Chemistry, Institute of Biochemistry, BOKU University, 1190 Vienna, Austria.
Abstract:
Chimeric antigen receptor (CAR) T cells have shown remarkable response rates in hematological malignancies. In contrast, CAR T cell treatment of solid tumors is associated with several challenges, in particular the expression of most tumor-associated antigens at lower levels in vital organs, resulting in on-target/off-tumor toxicities. Thus, innovative approaches to improve the tumor specificity of CAR T cells are urgently needed. Based on the observation that many human solid tumors activate epidermal growth factor receptor (EGFR) on their surface through secretion of EGFR ligands, we developed an engineering strategy for CAR-binding domains specifically directed against the ligand-activated conformation of EGFR. We show, in several experimental systems, that the generated binding domains indeed enable CAR T cells to distinguish between active and inactive EGFR. We anticipate that this engineering concept will be an important step forward to improve the tumor specificity of CAR T cells directed against EGFR-positive solid cancers.
Insights
Engineered chimeric antigen receptor (CAR) T-cells can now distinguish between active and inactive epidermal growth factor receptor (EGFR). This improves CAR T-cell specificity for solid tumors, reducing toxicities.
Area of Science:
- Immunotherapy
- Oncology
- Molecular Engineering
Background:
- Chimeric antigen receptor (CAR) T-cell therapy shows promise in blood cancers but faces challenges in solid tumors.
- On-target/off-tumor toxicities arise from tumor-associated antigens expressed in vital organs.
Purpose of the Study:
- To develop innovative strategies to enhance the tumor specificity of CAR T-cells.
- To engineer CAR T-cells capable of distinguishing between active and inactive epidermal growth factor receptor (EGFR) on tumor cells.
Main Methods:
- Developed novel CAR-binding domains targeting the ligand-activated conformation of EGFR.
- Tested the engineered CAR T-cells in experimental systems to assess specificity.
Main Results:
- The engineered binding domains successfully enabled CAR T-cells to differentiate between active and inactive EGFR.
- Demonstrated improved tumor specificity in experimental models.
Conclusions:
- This engineering strategy represents a significant advancement for CAR T-cell therapy in EGFR-positive solid tumors.
- The approach is anticipated to reduce on-target/off-tumor toxicities, improving treatment safety and efficacy.
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